The Latest Advances in the Treatment of Glioblastoma Multiforme (GBM), a Brain Tumor

Where Are We with Glioblastoma in 2026? A Comprehensive Guide from Diagnosis to Treatment and New Research

Glioblastoma (glioblastoma multiforme, GBM) is the most common malignant primary brain tumor in adults. Standard treatment is still maximally safe surgery, followed by radiation therapy and temozolomide; in eligible patients, electrical-field therapy called TTFields is added. The greatest change in recent years has been in diagnosis: since 2021, the diagnosis of “glioblastoma” has been used only for tumors without an IDH mutation, and treatment decisions are based on molecular testing. In this article, you will find together what the disease is, what standard treatment achieves, the options in case of recurrence, and the realistic status of new research such as CAR-T cells, vaccines, and proton therapy. the general symptoms and stages of brain tumors, molecular diagnosis and personalized treatment in glioblastoma and new treatments in 2026 for IDH-wildtype high-grade gliomas in separate articles.

Why is this topic important?

Glioblastoma accounts for 52.2% of malignant primary brain and spinal cord tumors in the United States; approximately 3.3 new diagnoses are made per 100,000 people each year, and the median age at diagnosis is 66. The disease progresses rapidly, and because tumor cells spread in a diffuse, infiltrative manner through the surrounding brain tissue, the tumor cannot be completely removed by surgery. According to U.S. cancer registries, approximately 43% of patients survive one year and 7% survive five years.

These figures represent averages; the course can vary greatly from one patient to another. Younger age, good overall condition, the ability to achieve extensive tumor removal, and MGMT methylation are associated with longer survival. In clinical studies, the proportion of patients surviving beyond five years is around 10% with standard treatment and approximately 13% when TTFields is added. Therefore, accurate molecular diagnosis, treatment planned by an experienced team, good symptom management, and access to appropriate clinical trials directly affect the course of the disease and quality of life.

What is the latest state of glioblastoma treatment?

As of 2026, standard treatment for glioblastoma is maximally safe surgery, radiation therapy together with temozolomide, followed by temozolomide maintenance and TTFields in eligible patients. Lomustine may be added in selected patients with methylated MGMT. CAR-T cells, vaccines, and proton dose escalation are promising but remain in the research stage; clinical trials are the safest way to access these treatments.

What is glioblastoma? The definition changed in 2021

Glioblastoma is a tumor originating from glial cells, the brain’s supporting cells, most commonly astrocytes. In the past, all astrocytic tumors that appeared most aggressive (grade 4) under the microscope were called glioblastoma. The WHO’s 2021 classification changed this definition: glioblastoma is now used only for adult IDH-wildtype tumors (without a mutation in the IDH gene). Tumors carrying an IDH mutation that were formerly called “secondary glioblastoma” are now considered a separate disease, IDH-mutant grade 4 astrocytoma, and their course is generally slower, with different treatment options.

There is another consequence of the new definition: an IDH-wildtype astrocytoma that appears grade 2 or 3 under the microscope is also considered and treated as glioblastoma if it carries a TERT promoter mutation, EGFR gene amplification, or gain of chromosome 7 with loss of chromosome 10 (+7/−10). Therefore, molecular testing of the tissue sample has become essential for diagnosis (next-generation sequencing (NGS)).

The frequencies of markers vary among studies. The scope of molecular testing differs from center to center; check your report to see which tests were performed.

What are the symptoms of glioblastoma, and how is it diagnosed?

Symptoms generally worsen over days or weeks and vary depending on the tumor's location. The most common include:

• Headache, particularly one that worsens in the morning and is accompanied by nausea and vomiting
• Seizure; may be the first symptom in approximately one-quarter of patients
• Weakness in an arm or leg, or speech or visual disturbances
• Forgetfulness, difficulty concentrating, and changes in personality and behavior

The first step in diagnosis is a contrast-enhanced brain MRI. On MRI, glioblastoma typically appears as a mass with a necrotic center, a contrast-enhancing rim, and marked surrounding edema. Perfusion MRI, MR spectroscopy, and, at some centers, amino acid PET may provide additional information; however, a definitive diagnosis is always made by tissue examination. If the tumor is in a location where it cannot be safely removed, a sample is obtained by stereotactic needle biopsy .

Surgery: Why is it often impossible to remove the entire tumor?

Glioblastoma cells spread into the surrounding healthy brain tissue in the form of fine extensions; tumor cells are also present beyond the boundary visible on MRI. Therefore, the goal of surgery is not to “remove everything,” but to safely remove as much of the contrast-enhancing mass as possible while preserving functions such as speech, movement, and vision. Surgery both reduces intracranial pressure and symptoms and provides sufficient tissue for molecular testing.

The amount of tumor removed is associated with survival. Therefore, methods such as 5-ALA (fluorescence-guided surgery), intraoperative MRI, neuronavigation, neuromonitoring, and awake surgery for tumors near the speech centers are used during surgery. In a randomized study of 5-ALA, the rate of complete removal of the contrast-enhancing tumor increased from 36% to 65%, and the proportion of patients alive without progression at 6 months increased from 21.1% to 41.0%. “Supramaximal” surgery, in which tissue beyond the contrast-enhancing area (the FLAIR area) is also removed, is being investigated in suitable patients; however, only provided that the risk of functional loss is not increased.

Standard postoperative treatment: the Stupp protocol

Usually 3–6 weeks after surgery, radiation therapy is administered over 6 weeks, every weekday, for a total of 30 sessions (60 Gy); during this period, temozolomide is also taken as a pill every day. After a break of approximately 4 weeks, temozolomide is continued on the first 5 days of 28-day cycles, generally for 6 cycles. This regimen is based on the phase 3 study published in 2005 and led by Roger Stupp, and it still forms the foundation of standard treatment.

Doses are calculated according to body surface area and adjusted according to blood values. For the relationship between temozolomide and food, you can consult the fasting-with-food table for oral cancer medications .

It is important to interpret the gains in the graph in absolute terms: in the Stupp study, adding temozolomide increased 2-year survival from 10.4% to 26.5% and 5-year survival from 1.9% to 9.8%. In other words, approximately 16 more out of every 100 patients reached 2 years, and 8 more reached 5 years. In relative terms, the risk of death decreased by approximately 37% (hazard ratio 0.63).

Why is MGMT so important?

Temozolomide causes damage by adding a methyl group to the tumor cell's DNA. The enzyme called MGMT can remove this methyl group and repair the damage. If the beginning region of the MGMT gene (the promoter) is silenced by methylation, less enzyme is produced, the damage cannot be repaired, and the drug is more effective. Therefore, MGMT methylation is the most important marker for predicting both the benefit from temozolomide and the course of the disease.

Although the contribution of temozolomide is small in unmethylated patients, standard treatment is continued at most centers because no better alternative has been proven, and these patients are particularly directed toward clinical trials. For example, the phase 3 Gliofocus study comparing the PARP inhibitor niraparib, specifically for this group, with temozolomide is ongoing; completion of the primary data is planned for the end of 2027. MGMT is not the only cause of resistance to temozolomide: An oxygen-deprived tumor environment, stem-cell-like tumor cells, other DNA repair pathways, and epigenetic changes also play a role (Aziz Sancar's study on temozolomide resistance).

TTFields (Optune): What does electric field therapy add?

TTFields (tumor treating fields) apply low-intensity, continuously alternating electric fields through four arrays attached to the head. These fields disrupt the cell-division mechanism (the spindle structure) in dividing cells; they do not significantly affect nondividing normal brain cells. The device is portable and must be worn for at least 18 hours per day for a benefit to be seen.

In the phase 3 EF-14 study of 695 patients who had completed radiation therapy, adding TTFields to maintenance temozolomide increased median survival from 16.0 to 20.9 months, progression-free survival from 4.0 to 6.7 months, and 5-year survival from 5% to 13%. The treatment may not be suitable for every patient because the study did not use a placebo device and because of the burden the device imposes on daily life. In the phase 3 TRIDENT study announced in June 2026, starting TTFields at the same time as radiation therapy did not prolong survival compared with starting it during the maintenance period (17.7 and 17.5 months). Thus, the place of TTFields has not changed: after radiation, together with maintenance temozolomide.

Treatment in older and patients with poorer general condition

In patients over 65 or those with a poorer general condition, the duration and burden of treatment become important. In a phase 3 study, adding temozolomide to short-course radiation (3 weeks, 40 Gy / 15 fractions) in patients over 65 extended median survival from 7.6 to 9.3 months; the difference was greater in patients with methylated MGMT (7.7 and 13.5 months). In very old or frail patients with methylated MGMT, temozolomide alone, and in unmethylated patients, short-course radiation therapy alone may be options. These decisions are based not on age but on the patient's general condition, expectations, and MGMT result.

Lomustine + temozolomide in younger patients with methylated MGMT

In the CeTeG/NOA-09 phase 3 study conducted in Germany, adding lomustine to standard temozolomide in 141 patients under 70 years of age who were in good general condition and had methylated MGMT extended median survival from 31.4 to 48.1 months. However, this was a small study, no difference in progression-free survival was observed, and side effects such as decreases in blood counts were more frequent. Therefore, some centers offer this treatment as an option for selected patients; it is not standard for everyone.

Further reading: Mechanisms of temozolomide action and resistance

Temozolomide becomes active in the body and adds a methyl group to guanine bases in DNA; the most important lesion is O6-methylguanine. As the cell attempts to repair this mismatched base, double-strand breaks form in the DNA and the cell undergoes programmed cell death (apoptosis). Because the MGMT enzyme directly repairs O6-methylguanine and prevents this process, it is the most important resistance mechanism. In addition, defects in the mismatch repair (MMR) system, a hypoxic tumor microenvironment, treatment-resistant glioma stem cells, microRNAs, and epigenetic changes can also cause resistance. After temozolomide, numerous new mutations (hypermutation) may develop in some tumors; this is important when planning treatment for recurrence. You can find more information in our article on Aziz Sancar and glioblastoma, in which we evaluate claims in this field from mouse experiments to patients. our article on Aziz Sancar and glioblastoma You can find more information.

Follow-up: Is every growth on MRI a recurrence?

After radiation therapy, MRI is generally repeated every 2–3 months. Particularly during the first 12 weeks after radiation and temozolomide have ended, the tumor may appear to have grown in approximately 20–30% of patients because of treatment-related inflammation and edema. This is called pseudoprogression ; it is more common in patients with methylated MGMT and often regresses spontaneously. Months or years later, radiation-related tissue damage (radiation necrosis) can also mimic recurrence. Therefore, the international RANO 2.0 criteria recommend confirmation with a second MRI at a short interval in the event of suspicious growth, rather than changing treatment immediately. Perfusion MRI, MR spectroscopy, amino acid PET, and, if necessary, repeat tissue sampling can help distinguish between them.

What options are available if the disease recurs?

Glioblastoma recurs in most patients after standard treatment, usually near the original tumor site. There is no single standard for treatment of recurrence; the decision is made by a multidisciplinary tumor board based on the tumor's size and location, previous treatments, the time elapsed, the patient's general condition, and preferences.

Targeted therapies: Who benefits?

Drugs targeting the most common genetic alterations in glioblastoma (such as EGFR amplification and PTEN loss) have not extended survival to date. Reasons include the drugs' inability to cross the blood–brain barrier sufficiently and the great genetic diversity of cells within the tumor. However, targeted therapies are a real option for a small group of patients:

• BRAF V600E mutation: Dabrafenib + trametinib has been approved in the United States since 2022 for all solid tumors carrying this mutation. The tumor shrank in approximately one-third of patients with high-grade glioma (tumor-agnostic cancer treatments).
• NTRK fusion: Larotrectinib and entrectinib may be used for this very rare alteration.
• High tumor mutational burden: Unlike other cancers, hypermutated tumors that develop after temozolomide mostly do not respond to immunotherapy; therefore, this is not considered a rationale for immunotherapy alone.

Vorasidenib, used in IDH-mutant gliomas, was approved in 2024 only for grade 2 IDH-mutant astrocytoma and oligodendroglioma; it has no role in IDH-wild-type glioblastoma. This distinction demonstrates the practical importance of the 2021 classification.

Immunotherapy, vaccines, and cell therapies: A realistic picture

The brain is an organ in which immune-system activity is limited; glioblastoma also creates an environment that suppresses immune cells. Therefore, immune drugs that have achieved major success in other cancers have not produced the expected results in glioblastoma. Nevertheless, this is the area with the most intensive research (immunotherapies and cancer vaccines).

• Immune checkpoint drugs: Nivolumab did not extend survival in either recurrent disease or newly diagnosed disease in three large phase 3 studies (CheckMate 143, 498, and 548). In patients with unmethylated MGMT, using nivolumab instead of temozolomide reduced median survival from 14.9 months to 13.4 months. In a small study of 35 patients who received pembrolizumab before surgery, median survival increased from 7.5 months to 13.7 months; this approach is being tested in larger studies.
• Dendritic cell vaccine (DCVax-L): In a phase 3 study of 331 patients, median survival was 19.3 months in newly diagnosed glioblastoma and 13.2 months in recurrent disease. However, the results were compared not with the study's own control group but with external controls taken from other studies, and this method was strongly criticized. The company applied to the United Kingdom's medicines regulator (MHRA) in December 2023; as of August 2026, no decision had been announced.
• Personalized peptide and mRNA vaccines: Vaccines designed from the tumor's own mutations generate immune responses in early studies; their effect on survival is not yet known (personalized peptide vaccine).
• CAR-T cells: In 2024, marked tumor shrinkage within days after administration into the cerebrospinal fluid was reported with CAR-T cells targeting EGFR and IL13Rα2. In the dual-target CAR-T study updated at ASCO 2026, median survival among 18 patients was 12.0 months, and the proportion alive at 18 months was 28%; one patient has maintained a response for 33 months. Responses are short-lived in most patients, and transient symptoms of brain inflammation occurred in all patients (dual-target CAR-T, B7-H3-targeted CAR-T).
• Oncolytic viruses: The genetically modified herpes virus teserpaturev, which multiplies in and destroys tumor cells, received conditional approval in Japan in 2021 after a 1-year survival rate of 84.2% in a phase 2 study of 19 patients. It is not approved in other countries.

Innovations in radiation therapy and drug delivery

Proton therapy: In the proton arm of the phase 2 NRG BN001 study (193 patients), increasing the dose from 60 Gy to 75 Gy increased median survival from 22.0 months to 22.8 months and 2-year survival from 43.1% to 49.9%; however, the difference did not reach the threshold for statistical significance, and dose escalation with photon radiation showed no benefit in the same study. The result was considered a “signal,” and a phase 3 study is being planned.

Radiation tiles placed during surgery (GammaTile): Small radiation sources placed in the cavity after tumor removal start radiation immediately, without waiting for wound healing. In the 67-patient GESTALT study, rapid regrowth before radiation began occurred in only 6% of patients (50–70% in previous series); the comparison is indirect, and the randomized phase 3 BRIDGES study has begun (GammaTile in brain metastases).

Opening the blood–brain barrier: An ultrasound device implanted in the skull (SonoCloud-9) temporarily opens the barrier before each drug administration, enabling drugs such as carboplatin, which normally penetrate the brain poorly, to reach the tumor. The phase 3 SONOBIRD study of 560 patients, comparing this method with standard chemotherapy in recurrent glioblastoma, is still recruiting patients.

Managing symptoms and quality of life

Glioblastoma treatment is not limited to tumor-directed therapy; effective symptom management directly affects both quality of life and the ability to continue treatment.

• Brain edema and steroids: Edema around the tumor increases headaches and neurological symptoms. increases headaches and neurological symptoms. Dexamethasone should be used at the lowest effective dose and for the shortest possible time; long-term use at high doses increases the risk of muscle weakness, high blood sugar, and infection.
• Seizures: In patients who have had seizures, medications with few drug interactions, such as levetiracetam, are preferred. Preventive antiseizure medication is generally not recommended in patients who have never had a seizure. Consult your doctor about driving restrictions after a seizure.
• Risk of blood clots: The risk of blood clots in the legs and lungs is high in glioblastoma; swelling and pain in the leg or sudden shortness of breath requires urgent evaluation.
• Fatigue, thinking, and memory: Fatigue is very common. Cognitive rehabilitation and mental exercises may support daily functioning.
• Rehabilitation and movement: Physical, speech, and occupational therapy should be planned from the time of diagnosis (exercise and rehabilitation in patients with brain tumors).
• Psychological support and caregivers: Depression and anxiety are common among patients and their loved ones; personality changes can also be challenging for the family. Psychological support and caregiver support should be part of treatment. Fear of recurrence can also be addressed separately.
• Palliative care: Palliative care is not only end-of-life care; from the time of diagnosis, it strengthens symptom management, decision-making processes, and family support (access to palliative care).

Questions you can ask your doctor

• What are the IDH, MGMT, TERT, EGFR, and BRAF results for my tumor? Was comprehensive molecular testing performed?
• How much of the tumor could be removed? Is there residual tumor on the postoperative MRI?
• What will my radiotherapy and temozolomide plan be? Are TTFields suitable for me?
• Based on my MGMT result, should lomustine be added, or is another option available?
• Is there a clinical trial I can participate in? Should we discuss this now or at recurrence?
• How often will follow-up MRIs be performed? How will we assess the possibility of pseudoprogression?
• Which symptoms should prompt me to call immediately? How should I use my steroid and antiseizure medication?

Frequently Asked Questions

Can glioblastoma be completely cured?

At present, glioblastoma is a disease that cannot be completely cured in most patients; however, the disease can be controlled with treatment and survival can be prolonged. With standard treatment, approximately 10% of patients survive beyond 5 years, compared with approximately 13% when TTFields is added. Younger age, good general condition, extensive surgery, and MGMT methylation are associated with longer survival.

How long does treatment last after surgery?

Three to six weeks after surgery, radiation therapy is administered for 6 weeks together with temozolomide every day. After an interval of approximately 4 weeks, temozolomide is generally given for 5 days every 28 days for 6 cycles; in eligible patients, TTFields is used together with it. The total duration is usually 9–10 months.

Is TTFields suitable for everyone?

TTFields prolonged survival in patients who had completed radiation therapy and were receiving maintenance temozolomide. It must be worn for at least 18 hours a day, the hair must be kept shaved, and the device must be carried; therefore, it is evaluated together with the patient's lifestyle and preferences. The TRIDENT study did not show an additional benefit from starting it at the same time as radiation therapy.

What is done if glioblastoma recurs?

First, it is determined whether the growth seen on MRI represents true recurrence or a treatment-related change. Options include repeat surgery, repeat radiation therapy, lomustine, retreatment with temozolomide, bevacizumab, targeted drugs for rare molecular alterations, and clinical trials. The decision is made individually by the tumor board.

Glossary

Glioblastoma (GBM)

The most common malignant primary brain tumor in adults; since 2021, only IDH-wildtype grade 4 tumors.

IDH-wildtype

The absence of mutations in the IDH1 and IDH2 genes; a fundamental condition for the diagnosis of glioblastoma.

MGMT promoter methylation

Silencing of the DNA-repair gene MGMT; it predicts the benefit from temozolomide and the disease course.

Stupp protocol

The standard treatment consisting of 6 weeks of radiation therapy with daily temozolomide, followed by 6 cycles of maintenance temozolomide.

TTFields (tumor-treating fields)

A low-intensity electric-field treatment applied with transducer arrays worn on the head that disrupts the division of dividing cells.

5-ALA

A substance taken orally before surgery that makes tumor cells appear bright under microscope light; it enables more extensive resection.

Pseudoprogression

The appearance of tumor growth on MRI during the first months after treatment due to treatment-related inflammation and edema.

Radiation necrosis

Tissue damage that may develop months or years after radiation therapy and can mimic recurrence.

RANO

International criteria used to evaluate treatment response and progression in brain tumors.

CAR-T cell

A cell therapy obtained by modifying the patient's own T cells in the laboratory so that they recognize a specific target in the tumor.

Blood–brain barrier

A blood-vessel-wall structure that protects the brain from harmful substances in the blood while also limiting the passage of many drugs into the brain.